Compounds based on the ergoline ring system ##SPC1##
Have a suprising variety of pharmaceutical activities. For example, lysergic and isolysergic acid are 8-carboxy-6-methyl-9-ergolenes. The amides of lysergic acid, many of which have valuable and unique pharmacologic properties, include the naturally occurring oxytocic alkaloids - ergocornine, ergokryptine, ergonovine, ergocristine, ergosine, ergotamine, etc. -- and synthetic oxytocics such as methergine, as well as the synthetic hallucinogen -- lysergic acid diethylamide or LSD. The corresponding amides of 6-methyl-8-carboxyergoline, known generically as dihydroergot alkaloids, are oxytocic agents of lower potency and also lower toxicity than the ergot alkaloids themselves. Recently, it has been found by Clemens, Semonsky, Meites and their various co-workers, that many ergot-related drugs have activity as prolactin inhibitors including ergocornine, dihydroergocornine, 2-bromo-.alpha.-ergokryptine and d-6-methyl-8-cyanomethylergoline. References embodying some of the newer findings in this field of ergoline pharmacology are the following: Nagasawa and Meites, Proc. Soc. Exp't'l. Biol. Med, 135, 469 (1970); Lutterbeck et al., Brit. Med. J., 228, (July 24, 1971); Heuson et al., Europ. J. Cancer, 353 (1970); Coll. Czech, Chem. Commun., 33, 577 (1968); Nature, 221, 666 (1969); Seda et al., J. Reprod. Fert., 24, 263 (1971); Mantle and Finn, id, 441; Semonsky and co-workers, Coll. Czech. Chem. Comm., 36, 2200 (1971); Schaar and Clemens, Endocr., 90, 285-8 (1972); Clemens and Schaar, Proc. Soc. Exp. Biol. Med., 139, 659-662 (1972) and Sweeney, Clemens, Kornfeld and Poore, 64th Annual Meeting, American Association Cancer Research, April, 1973. Recently issued patents in the field of erogoline derivatives or lysergic acid derivatives include the following: U.S. Pat. No. 3.704,233, U.S. Pat. No. 3,709,891, U.S. Pat. No. 3,585,201, U.S. Pat. No. 3,666,762, U.S. Pat. No. 3,586,683, U.S. Pat. No. 3,717,640, and U.s. Pat. No. 3,592,816.
Only a few 8,8-disubstituted ergolines have been prepared. A majority of these compounds also have a substituent on the indole nitrogen thus yielding a 1,8,8-tri-substituted derivative. For example, Baker et al. publishing in Molecular Pharmacology, 9, 23 (1973) reported 1,8-dimethyl-D-lysergic acid p-bromanilide. This compound showed no hallucinogenic activity unlike D-lysergic acid p-bromanilide. The same compound is mentioned in Science, 178, 614 (1972). Troxler and Hofmann, Helvetica Chemica Acta, 40, 1722 (1957) prepared the 8-methyl derivative of D-isolysergic acid diethylamide, stating that they were, however, unable to obtain substitution at C.sub.8 using dihydrolysergic acid methyl ester and the alkylating agent used successfully with lysergic acid itself; to wit, methyliodide and potassium amide. These authors also prepared 8-ethyl-D-isolysergic acid diethylamide and the 1,8-dimethyl-D-isolysergic acid diethylamide. There is no mention in the literature of an 8,8-disubstituted-9-ergolene in which the substituents at 8 are other than amide groups and in which the 1-position is not substituted. 6-Methyl-8,8-disubstituted ergolines are not mentioned in the literature.